1. Field of the Invention
The present invention relates to acetylcholine, cholinergic signal transduction, and bile acids. In another aspect, the present invention relates to hybrid molecules, the synthesis of hybrid molecules from a progenitor cholinergic agent and a bile acid, and compositions and methods comprising said hybrid molecules. In even another aspect, the present invention relates to hybrid cholinergic molecules, compositions comprising hybrid cholinergic molecules, and methods of using said molecules and compositions as agonists or antagonists of muscarinic receptor-dependent signal transduction. In still another aspect, the present invention relates to hybrid cholinergic molecules, compositions comprising said molecules, and methods of treating a medical disorder comprising administration of these molecules and/or compositions.
2. Description of the Related Art
Acetylcholine (ACh) serves as the neurotransmitter at all autonomic ganglia, at the postganglionic parasympathetic nerve endings, and at the postganglionic sympathetic nerve endings innervating the eccrine sweat glands. Two different types of cholinergic receptors for ACh, the nicotinic and muscarinic receptors, exist on the postganglionic neurons within the autonomic ganglia and at the postjunctional autonomic effector sites. The nicotinic receptors are stimulated predominantly by nicotine and are found in the synapses between the preganglionic and postganglionic neurons of both the sympathetic and parasympathetic nervous systems, and are also present in many membranes of skeletal muscle fibers at the neuromuscular junction. The muscarinic receptors are stimulated primarily by the alkaloid muscarine and are found in all effector cells stimulated by the postganglionic neurons of the parasympathetic nervous system, and effector cells stimulated by the postganglionic cholinergic neurons of the sympathetic nervous system. Clearly, cholinergic receptors play an important role in the functioning of muscles, organs and the central nervous system. Cross-talk also exists between cholinergic receptors and the receptors of other neurotransmitters such as dopamine, serotonin and catecholamines.
Muscarinic cholinergic receptors can be characterized pharmacologically by their interaction with a variety of agonists and antagonists. Molecular cloning studies have revealed the existence of five muscarinic receptor gene, designated M1-M5, base on the order of the cloning of the genes.
Disruption of the cholinergic neurotransmitter signalling system has been implicated in numerous medical conditions. For example, disruption of cholinergic signal transduction has been implicated in age related central nervous system (CNS) dysfunction, such as cognitive decline and Alzheimer""s disease. Alzheimer""s disease is combined with, and also most likely caused by, an up to 90% degeneration of the muscarinic cholinergic neurons in nucleus basalis which project to the prefrontal cortex and hippocampus and have a general stimulatory effect on the cognitive functions, namely learning, association, consolidation and recognition, of the forebrain and hippocampus.
It is a characteristic of Alzheimer""s disease that although the cholinergic neurons degenerate, the postsynaptic muscarinic receptors in the forebrain and hippocampus still exist. Muscarinic cholinergic agonists are believed to be useful in the treatment of Alzheimer""s disease, in halting its progression, and in improving the cognitive functions of elderly people. In addition to treating cognitive decline, muscarinic agonists are useful as analgesic agents in the treatment of severely painful conditions, with the analgesia produced being comparable to that of opiate analgesics.
Agents that act as muscarinic receptor antagonistics are useful in the treatment of glaucoma, psychotic conditions, anxiety, mania, bipolar disorder, schizophrenia or schizophreniform conditions, depression, sleep disorders, epilepsy, cerebral ischemia, and diseases associated with altered mobility or tone of smooth muscle, such as, gastrointestinal motility disorders and chronic obstructive airways disease.
Raufman et al, 1998, Am. J. Physiol. 274 (6 Pt 1):G997-1004, disclose a possible role for the bile acid lithocholyltaurine as a partial agonist for muscarinic cholinergic receptors in gastric chief cells.
Kadlubowski et al., 1984, Acta. Physiol. Pol. September-December; 35(5-6):491-9 disclose action of select drugs on the autonomic system under the influence of the bile acids 3,12-dihydroxycholanic acid (deoxycholic), 3,7,12-trihydroxycholanic acid (cholic), and 3,7,12-triketocholanic acid (dehydrocholic).
Szkudlinski, 1984, Acta. Physiol. Pol. September-December; 35(5-6):500-8 discloses the effects of bile acids (deoxycholic, cholic, and dehydrocholic) on the action of select autonomic system drugs. Results therein suggest bile acids increase the effect of acetylcholine on the intestine.
U.S. Pat. No. 6,124,312, issued Sep. 26, 2000, to Mitch et al., discloses use of heterocyclic 2-aza-bicyclo-[2.2.1]-heptane compounds in modulating a muscarinic receptor.
U.S. Pat. No. 6,060,473, issued May 9, 2000, to Shen et al., discloses use of 7-azabicyclo-[2.2.1]-heptane and -heptene derivatives that may be administered to treat disorders associated with a decrease or increase in cholinergic activity.
U.S. Pat. No. 6,093,733, issued Jul. 25, 2000, to Villalobos et al., discloses a class of partial or full muscarinic receptor agonists useful for treatment or prevention of diseases/syndromes characterized by excessive cholinergic activity.
EP 0,301,392 (A1) published Feb. 1, 1989, Carman et al., discloses a pharmaceutical composition for intra-nasal administration comprising GO-Releasing hormone, a cholinergic agent, and a bile salt.
In spite of advancements in the art, many compounds that affect muscarinic cholinergic receptor activity are associated with side effects attributed to undesired modulation of the muscarinic cholinergic receptors. Such undesired modulation may cause effects such as, excessive salivation and gastrointestinal upset. Thus, there is a need in the art for new cholinergic agents having high potency and a favorable side effect profile.
There is another need in the art for methods of making cholinergic agents, wherein the agents are hybrid molecules derived from a progenitor cholinergic agent and a bile acid.
There is even another need in the art for compositions comprising cholinergic agents, wherein the agents are hybrid molecules derived from a progenitor cholinergic agent and a bile acid.
There is still another need in the art for methods of making such compositions.
There is yet another need in the art for methods of treating a patient having a disorder, wherein the methods comprise administration of a composition comprising a cholinergic agent, wherein the agent is a hybrid molecule derived from a progenitor cholinergic agent and a bile acid.
These and other needs will become apparent to those of skill in the art upon review of this specification, including its drawings, claims and appendix.
It is an object of the present invention to provide cholinergic agents that are hybrids synthesized from a progenitor cholinergic agent and a bile acid.
It is another object of the present invention to provide methods of making cholinergic agents, wherein the agents are hybrid molecules derived from a progenitor cholinergic agent and a bile acid.
It is even another object of the present invention to provide compositions comprising said cholinergic agents.
It is still another object of the present invention to provide methods of making such compositions.
It is yet another object of the present invention to provide methods of treating a patient having a disorder wherein the method comprises administration of a composition comprising a cholinergic agent, wherein the agent is a hybrid molecule derived from a progenitor cholinergic agent and a bile acid.
One embodiment of the present invention is directed to novel cholinergic agents. Generally the agents are hybrid/chimeric molecules synthesized from a progenitor cholinergic agent and a bile acid. The progenitor cholinergic agent may be any cholinergic agent including, but not limited to, acetylcholine, atropine, N-methylscopolamine and carbamylcholine, and a bile acid. The bile acid may be any bile acid including, but not limited to, the major bile acids, such as the cholic, deoxycholic, chenodeoxycholic, lithocholic, ursocholic and ursodeoxycholic acids. In a preferred embodiment, the progenitor cholinergic agent is acetylcholine and the bile acid is lithocholic acid. The hybrid cholinergic molecules of the invention interact with a cholinergic receptor and may function as either cholinergic agonists, or cholinergic antagonists.
Another embodiment of the present invention is directed to methods of making a hybrid/chimeric cholinergic agent. Generally the methods comprise the steps of:
1. formylation of a bile acidxe2x86x92product A;
2. product A+a progenitor cholinergic agentxe2x86x92product B;
3. product B+methanesulfonic acidxe2x86x92hybrid cholinergic agent.
Even another embodiment of the present invention is directed to compositions comprising a cholinergic agent. Generally the compositions of the invention comprise cholinergic agents that are hybrid/chimeric molecules synthesized from a progenitor cholinergic agent and a bile acid. A particularly preferred composition of the invention comprises lithocholylcholine, a hybrid cholinergic agent synthesized from acetylcholine and lithocholic acid.
Still another embodiment of the present invention is directed to methods of making such compositions.
Yet another embodiment of the present invention is directed to methods of treating a patient. Generally, the methods comprise administering a hybrid/chimeric molecule that functions as a cholinergic agent. A particularly preferred agent of the invention is lithocholylcholine. The patient may be any mammal, but is generally a human. The method of the invention is useful for treating a patient having a medical condition wherein the sympathetic nervous system is affected.
These and other embodiments of the present invention will become apparent to those of skill in the art upon review of this specification, including its drawings, appendix, and claims.